Microenvironment drives cell state, plasticity, and drug response in pancreatic cancer.

Prognostically relevant RNA expression states exist in pancreatic ductal adenocarcinoma (PDAC), but our understanding of their drivers, stability, and relationship to therapeutic response is limited. To examine these attributes systematically, we profiled metastatic biopsies and matched organoid models at single-cell resolution. In vivo, we identify a new intermediate PDAC transcriptional cell state and uncover distinct site- and state-specific tumor microenvironments (TMEs). Benchmarking models against this reference map, we reveal strong culture-specific biases in cancer cell transcriptional state representation driven by altered TME signals. We restore expression state heterogeneity by adding back in vivo-relevant factors and show plasticity in culture models. Further, we prove that non-genetic modulation of cell state can strongly influence drug responses, uncovering state-specific vulnerabilities. This work provides a broadly applicable framework for aligning cell states across in vivo and ex vivo settings, identifying drivers of transcriptional plasticity and manipulating cell state to target associated vulnerabilities.

Molecular Pathways of Colon Inflammation Induced by Cancer Immunotherapy.

Checkpoint blockade with antibodies specific for the PD-1 and CTLA-4 inhibitory receptors can induce durable responses in a wide range of human cancers. However, the immunological mechanisms responsible for severe inflammatory side effects remain poorly understood. Here we report a comprehensive single-cell analysis of immune cell populations in colitis, a common and severe side effect of checkpoint blockade. We observed a striking accumulation of CD8 T cells with highly cytotoxic and proliferative states and no evidence of regulatory T cell depletion. T cell receptor (TCR) sequence analysis demonstrated that a substantial fraction of colitis-associated CD8 T cells originated from tissue-resident populations, explaining the frequently early onset of colitis symptoms following treatment initiation. Our analysis also identified cytokines, chemokines, and surface receptors that could serve as therapeutic targets for colitis and potentially other inflammatory side effects of checkpoint blockade.

RECQL5 controls transcript elongation and suppresses genome instability associated with transcription stress.

RECQL5 is the sole member of the RECQ family of helicases associated with RNA polymerase II (RNAPII). We now show that RECQL5 is a general elongation factor that is important for preserving genome stability during transcription. Depletion or overexpression of RECQL5 results in corresponding shifts in the genome-wide RNAPII density profile. Elongation is particularly affected, with RECQL5 depletion causing a striking increase in the average rate, concurrent with increased stalling, pausing, arrest, and/or backtracking (transcription stress). RECQL5 therefore controls the movement of RNAPII across genes. Loss of RECQL5 also results in the loss or gain of genomic regions, with the breakpoints of lost regions located in genes and common fragile sites. The chromosomal breakpoints overlap with areas of elevated transcription stress, suggesting that RECQL5 suppresses such stress and its detrimental effects, and thereby prevents genome instability in the transcribed region of genes.

Quantum simulation of 2D antiferromagnets with hundreds of Rydberg atoms.

Quantum simulation using synthetic systems is a promising route to solve outstanding quantum many-body problems in regimes where other approaches, including numerical ones, fail1. Many platforms are being developed towards this goal, in particular based on trapped ions2-4, superconducting circuits5-7, neutral atoms8-11 or molecules12,13. All of these platforms face two key challenges: scaling up the ensemble size while retaining high-quality control over the parameters, and validating the outputs for these large systems. Here we use programmable arrays of individual atoms trapped in optical tweezers, with interactions controlled by laser excitation to Rydberg states11, to implement an iconic many-body problem-the antiferromagnetic two-dimensional transverse-field Ising model. We push this platform to a regime with up to 196 atoms manipulated with high fidelity and probe the antiferromagnetic order by dynamically tuning the parameters of the Hamiltonian. We illustrate the versatility of our platform by exploring various system sizes on two qualitatively different geometries-square and triangular arrays. We obtain good agreement with numerical calculations up to a computationally feasible size (approximately 100 particles). This work demonstrates that our platform can be readily used to address open questions in many-body physics.

Elongation Factor TFIIS Prevents Transcription Stress and R-Loop Accumulation to Maintain Genome Stability.

Although correlations between RNA polymerase II (RNAPII) transcription stress, R-loops, and genome instability have been established, the mechanisms underlying these connections remain poorly understood. Here, we used a mutant version of the transcription elongation factor TFIIS (TFIISmut), aiming to specifically induce increased levels of RNAPII pausing, arrest, and/or backtracking in human cells. Indeed, TFIISmut expression results in slower elongation rates, relative depletion of polymerases from the end of genes, and increased levels of stopped RNAPII; it affects mRNA splicing and termination as well. Remarkably, TFIISmut expression also dramatically increases R-loops, which may form at the anterior end of backtracked RNAPII and trigger genome instability, including DNA strand breaks. These results shed light on the relationship between transcription stress and R-loops and suggest that different classes of R-loops may exist, potentially with distinct consequences for genome stability.

Association of Lateral Pelvic Lymph Nodes with Disease Recurrence and Organ Preservation in Patients with Distal Rectal Adenocarcinoma Treated with Total Neoadjuvant Therapy.

OBJECTIVE: Assess the significance of enlarged lateral lymph nodes (LLN) for disease recurrence, metastasis, and organ preservation in patients with rectal cancer. BACKGROUND: Optimal treatment of rectal adenocarcinoma involving LLN is subject to debate. METHODS: A post hoc analysis of the OPRA trial, a multicenter study of patients with rectal cancer treated with total neoadjuvant therapy (TNT) followed by total mesorectal excision or watch-and-wait management. We analyzed the association of visible LLN (LLN+), LLN≥7 mm (short axis) on baseline MRI, and LLN≥4 mm on restaging MRI with recurrence, metastasis, and rectum preservation. RESULTS: At baseline, 57 out of 324 (18%) patients had LLN+. In 30 (53%) of 57 patients with LLN+ on baseline MRI, the LLN disappeared after TNT. Disease recurrence in LLN was rare (3.5% of patients with LLN+ and 0.4% of patients with LLN-). All patients with recurrence in LLN also had distant metastasis. The rate of organ preservation was significantly lower in patients with LLN≥4 mm on restaging MRI (P=0.013). We found no significant differences in rates of local recurrence or metastasis between patients with LLN+ vs. LLN- and in patients with LLN≥7 vs.<7 mm on baseline MRI. LLN dissection was performed in 3 patients; 2 of them died of distant metastasis. CONCLUSIONS: LLN involvement is not associated with disease recurrence or metastasis, but persistence of LLN≥4 mm after TNT is negatively associated with rectum preservation in patients with locally advanced rectal cancer treated with TNT. Dissection of lateral nodes likely benefits few patients.

Assessing Endoscopic Response in Locally Advanced Rectal Cancer Treated with Total Neoadjuvant Therapy: Development and Validation of a Highly Accurate Convolutional Neural Network.

BACKGROUND: Rectal tumors display varying degrees of response to total neoadjuvant therapy (TNT). We evaluated the performance of a convolutional neural network (CNN) in interpreting endoscopic images of either a non-complete response to TNT or local regrowth during watch-and-wait surveillance. METHODS: Endoscopic images from stage II/III rectal cancers treated with TNT from 2012 to 2020 at a single institution were retrospectively reviewed. Images were labelled as Tumor or No Tumor based on endoscopy timing (before, during, or after treatment) and the tumor's endoluminal response. A CNN was trained using ResNet-50 architecture. The area under the curve (AUC) was analyzed during training and for two test sets. The main test set included images of tumors treated with TNT. The other contained images of local regrowth. The model's performance was compared to sixteen surgeons and surgical trainees who evaluated 119 images for evidence of tumor. Fleiss' kappa was calculated by respondent experience level. RESULTS: A total of 2717 images from 288 patients were included; 1407 (51.8%) contained tumor. The AUC was 0.99, 0.98, and 0.92 for training, main test, and local regrowth test sets. The model performed on par with surgeons of all experience levels for the main test set. Interobserver agreement was good ( k = 0.71-0.81). All groups outperformed the model in identifying tumor from images of local regrowth. Interobserver agreement was fair to moderate ( k = 0.24-0.52). CONCLUSIONS: A highly accurate CNN matched the performance of colorectal surgeons in identifying a noncomplete response to TNT. However, the model demonstrated suboptimal accuracy when analyzing images of local regrowth.

Is White Evangelical Antistructural Theology Related to Poor Health Outcomes?

Policy Points White evangelical theology has an "antistructural" component. Counties with a high percentage of White evangelicals have higher mortality rates and more persons with fair/poor health. The potential influence of antistructural components in evangelical theology on decision making and resource allocation and, ultimately, the length and quality of life of community members presents a point of intervention for religious leaders and policymakers to improve population health. CONTEXT: Structural factors are important determinants of health. Because antistructuralism has been identified as a tenet of White evangelical theology, we explored if there is an association of the percentage of White evangelicals in a US county with two county health outcomes: premature mortality and percentage of fair/poor health. METHODS: Regression analysis was performed with data from 2022 County Health Rankings and the American Value Atlas from the Public Religion Research Institute. FINDINGS: Every percent of evangelicals in a county is associated with 4.01 more premature deaths per 100,000 population and 0.13% fair/poor health. After controlling for income, education, political ideology, and county school funding adequacy (a proxy for antistructuralism), the associations remain positive and significant. CONCLUSIONS: We hope these findings could inform dialogue and critical analysis among individuals of evangelical faith, particularly fundamental and Pentecostal subsets, regarding a belief system that is inclusive of individual dimensions and health-promoting structural policies like school funding, Medicaid expansion, and antipoverty programs. These findings also demonstrate the importance of considering cultural factors like religion and political ideology in population health outcomes research.

Endoscopic Predictors of Residual Tumor After Total Neoadjuvant Therapy: A Post Hoc Analysis From the Organ Preservation in Rectal Adenocarcinoma Trial.

BACKGROUND: Restaging endoscopy plays a critical role in selecting patients with locally advanced rectal cancer who respond to neoadjuvant therapy for nonoperative management. OBJECTIVE: This study evaluated the restaging endoscopic features that best predict the presence of residual tumor in the bowel wall. DESIGN: This was a post hoc analysis of a prospective randomized trial. SETTINGS: The Organ Preservation in Rectal Adenocarcinoma Trial randomly assigned patients across 18 institutions with stage II/III rectal adenocarcinoma to receive either induction or consolidation total neoadjuvant therapy. Surgeons completed a restaging tumor assessment form, which stratified patients across 3 tiers of clinical response. PATIENTS: Patients enrolled in the Organ Preservation in Rectal Adenocarcinoma Trial with a completed tumor assessment form were included. MAIN OUTCOME MEASURES: The main outcome was residual tumor, which was defined as either an incomplete clinical response or local tumor regrowth within 2 years of restaging. Independent predictors of residual tumor were identified using backward-selected multivariable logistic regression analysis. Subgroup analyses for complete and near complete clinical responders were performed. RESULTS: Surgeons completed restaging forms for 263 patients at a median of 7.7 weeks after neoadjuvant therapy; 128 patients (48.7%) had a residual tumor. On multivariable regression analysis, several characteristics of a near complete response, including ulcer (OR 6.66; 95% CI, 2.54-19.9), irregular mucosa (OR 3.66; 95% CI, 1.61-8.68), and nodularity (OR 2.96; 95% CI, 1.36-6.58), remained independent predictors of residual tumor. A flat scar was associated with lower odds of harboring residual disease (OR 0.32; 95% CI, 0.11-0.93) for patients categorized as clinical complete responders. LIMITATIONS: Limitations include analysis of endoscopic features at a single time point and ambiguities in tumor assessment form response criteria. CONCLUSIONS: Patients with ulcer, nodularity, or irregular mucosa, on restaging endoscopy have higher odds of residual tumor. Recognizing negative prognostic implications of these features will help surgeons better select candidates for nonoperative management and suggests that patients with high-risk characteristics would benefit from close interval surveillance. See Video Abstract . PREDICTORES ENDOSCPICOS DE TUMOR RESIDUAL DESPUS DE TERAPIA NEOADYUVANTE TOTAL UN ANLISIS POST HOC DEL ENSAYO DE PRESERVACIN DE RGANOS EN ADENOCARCINOMA RECTAL: ANTECEDENTES:La reestadificación por endoscopia juega un papel crítico en la selección de pacientes con cáncer de recto localmente avanzado que responden a la terapia neoadyuvante para el manejo no quirúrgico.OBJETIVO:Este estudio evaluó las características endoscópicas de reestadificación que mejor predicen la presencia de tumor residual en la pared intestinal.DISEÑO:Este fue un análisis post hoc de un ensayo prospectivo aleatorizado.ESCENARIO:El ensayo Organ Preservation in Rectal Adenocarcinoma aleatorizó a pacientes de 18 instituciones con adenocarcinoma de recto en estadio II/III para recibir terapia neoadyuvante total de inducción o consolidación. Los cirujanos completaron un formulario de reestadificación de evaluación del tumor, que estratificó a los pacientes en tres niveles de respuesta clínica.PACIENTES:Se incluyeron pacientes inscritos en el ensayo de preservación de órganos en adenocarcinoma rectal con un formulario de evaluación del tumor completado.PRINCIPALES MEDIDAS DE RESULTADO:El resultado principal fue presencia de tumor residual, que se definió como una respuesta clínica incompleta o un nuevo crecimiento local del tumor dentro de los dos años posteriores a la reestadificación. Los predictores independientes de tumor residual se identificaron mediante un análisis de regresión logística multivariable seleccionado hacia atrás. Se realizaron análisis de subgrupos para pacientes con respuesta clínica completa y casi completa.RESULTADOS:Los cirujanos completaron formularios de reestadificación para 263 pacientes en una mediana de 7.7 semanas después de la terapia neoadyuvante; 128 (48.7%) tenían tumor residual. En el análisis de regresión multivariable, varias características de una respuesta casi completa, incluyendo úlcera (OR 6.66; IC 95% 2.54-19.9), mucosa irregular (OR 3.66; IC 95% 1.61-8.68) y nodularidad (OR 2.96; IC 95% 1.36 -6.58) siguieron siendo predictores independientes de tumor residual. Una cicatriz plana se asoció con menores probabilidades de albergar enfermedad residual (OR 0.32; IC del 95 %: 0.11-0.93) para los pacientes clasificados como respondedores clínicos completos.LIMITACIONES:Las limitaciones de este estudio incluyen el análisis de las características endoscópicas en un solo momento y las ambigüedades en los criterios de respuesta.en la forma de evaluación del tumorCONCLUSIONES:Los pacientes con úlcera, nodularidad o mucosa irregular en la endoscopia de reestadificación tienen mayores probabilidades de tumor residual. El reconocer las implicaciones pronósticas negativas de estas características ayudará a los cirujanos a seleccionar mejor a los candidatos para el tratamiento no quirúrgico y sugiere que los pacientes con características de alto riesgo se beneficiarían de una vigilancia a intervalos estrechos. (Traducción-Dr. Jorge Silva Velazco ).

Model-driven mitigation measures for reopening schools during the COVID-19 pandemic.

Reopening schools is an urgent priority as the COVID-19 pandemic drags on. To explore the risks associated with returning to in-person learning and the value of mitigation measures, we developed stochastic, network-based models of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission in primary and secondary schools. We find that a number of mitigation measures, alone or in concert, may reduce risk to acceptable levels. Student cohorting, in which students are divided into two separate populations that attend in-person classes on alternating schedules, can reduce both the likelihood and the size of outbreaks. Proactive testing of teachers and staff can help catch introductions early, before they spread widely through the school. In secondary schools, where the students are more susceptible to infection and have different patterns of social interaction, control is more difficult. Especially in these settings, planners should also consider testing students once or twice weekly. Vaccinating teachers and staff protects these individuals and may have a protective effect on students as well. Other mitigations, including mask wearing, social distancing, and increased ventilation, remain a crucial component of any reopening plan.

Historical Perspectives: Malignancy in Crohn's Disease and Ulcerative Colitis.

While both Crohn' disease (CD) and ulcerative colitis (UC) are known to predispose patients to certain intestinal malignancies, the exact mechanism of carcinogenesis remains unknown and optimal screening guidelines have not been established. This article will explore the history of our understanding of intestinal malignancy in inflammatory bowel disease (IBD). To contextualize the medical community's difficulty in linking each condition to cancer, the first section will review the discovery of CD and UC. Next, we discuss early attempts to define IBD's relationship with small bowel adenocarcinoma and colorectal cancer. The article concludes with a review of each disease's surgical history and the ways in which certain procedures produced poor oncologic outcomes.

Label-Free SERS for Rapid Differentiation of SARS-CoV-2-Induced Serum Metabolic Profiles in Non-Hospitalized Adults.

COVID-19 represents a multi-system infectious disease with broad-spectrum manifestations, including changes in host metabolic processes connected to the disease pathogenesis. Understanding biochemical dysregulation patterns as a consequence of COVID-19 illness promises to be crucial for tracking disease course and clinical outcomes. Surface-enhanced Raman scattering (SERS) has attracted considerable interest in biomedical diagnostics for the sensitive detection of intrinsic profiles of unique fingerprints of serum biomolecules indicative of SARS-CoV-2 infection in a label-free format. Here, we applied label-free SERS and chemometrics for rapid interrogation of temporal metabolic dynamics in longitudinal sera of mildly infected non-hospitalized patients (n = 22), at 4 and 16 weeks post PCR-positive diagnosis, and compared them with negative controls (n = 8). SERS spectral markers revealed distinct metabolic profiles in patient sera that significantly deviated from the healthy metabolic state at the two sampling time intervals. Multivariate and univariate analyses of the spectral data identified abundance dynamics in amino acids, lipids, and protein vibrations as the key spectral features underlying the metabolic differences detected in convalescent samples and perhaps associated with patient recovery progression. A validation study performed using spontaneous Raman spectroscopy yielded spectral data results that corroborated SERS spectral findings and confirmed the detected disease-specific molecular phenotypes in clinical samples. Label-free SERS promises to be a valuable analytical technique for rapid screening of the metabolic phenotype induced by SARS-CoV-2 infection to allow appropriate healthcare intervention.

T1 Gastric Cancer Is Associated With a High Incidence of Regional Lymph Node Metastases.

INTRODUCTION: Early stage gastric cancer, particularly T1 disease, is associated with high recurrence-free and overall survival rates following resection with curative intent. However, rare cases of T1 gastric cancer have nodal metastasis and this is associated with poor outcomes. METHODS: Data from gastric cancer patients treated with surgical resection and D2 lymph node (LN) dissection at a single tertiary care institution from 2010 to 2020 were analyzed. Patients with early stage (T1) tumors were assessed in detail to identify variables associated with regional LN metastasis including histologic differentiation, signet ring cells, demographics, smoking history, neoadjuvant therapy, and clinical staging by endoscopic ultrasound (EUS). We used standard statistical techniques including Mann-Whitney U and Chi-squared tests. RESULTS: Of 426 patients undergoing surgery for gastric cancer, 34% (n = 146) were diagnosed with T1 disease on surgical pathology. Among 146 T1 (T1a, T1b) gastric cancers, 24 patients [(17%) T1a (n = 4), T1b (n = 20)] had histologically confirmed regional LN metastases. The age at diagnosis ranged between 19 and 91 y and 54.8% were male. Prior smoking status was not associated with nodal positivity (P = 0.650). Of the 24 patients with positive LN on final pathology, seven patients received neoadjuvant chemotherapy. EUS was performed on 98 (67%) of the 146 T1 patients. Of these patients, 12 (13.2%) had positive LN on final pathology; however, none (0/12) were detected on preoperative EUS. There was no association between node status on EUS and node status on final pathology (P = 0.113). The sensitivity of EUS for N status was 0%, specificity was 84.4%, negative predictive value was 82.2% and positive predictive value was 0%. Signet ring cells were identified in 42% of node negative T1 tumors and 64% of node positive T1 tumors (P = 0.063). For LN positive cases on surgical pathology, 37.5% had poor differentiation, 42% had lymphovascular invasion, and regional nodal metastases were associated with increasing T stage (P = 0.003). CONCLUSIONS: T1 gastric cancer is associated with a substantial risk (17%) of regional LN metastasis, when pathologically staged following surgical resection and D2 lymphadenectomy. Clinically staged N+ disease by EUS was not significantly associated with pathologically staged N+ disease in these patients.

Association of hospital volume with postoperative outcomes in Crohn's disease.

AIM: Most patients diagnosed with Crohn's disease (CD) require surgery during their lifetime. While the literature has shown that certain cancer patients have superior postoperative outcomes at high-volume hospitals, there remains a paucity of data on the hospital volume-outcome relationship in CD. Given the complexities in both medical and surgical management, this study aims to determine whether patients with CD have superior postoperative outcomes at high-volume hospitals. METHOD: A retrospective analysis of patients undergoing abdominal surgery for CD in New York hospitals between 2012 and 2018 was performed using data from the Statewide Planning and Research Cooperation System. Outcomes included postoperative mortality, 30-day readmission and postoperative complications. Using a penalized B-spline plot, high-volume centres were defined as those performing more than 160 abdominal surgeries for CD each year. RESULTS: A total of 13,221 surgeries were performed across 176 hospital centres in New York State. Of these, 73.9% of procedures occurred at low-volume centres. High-volume hospitals had lower in-hospital mortality (0.5% vs. 1.5%; p < 0.001) and 30-day readmission rates (8.3% vs. 10.4%; p < 0.001) than low-volume centres. Major postoperative complications and reoperation rates did not differ by hospital volume. On multivariate analysis, patients at high-volume hospitals had lower odds of in-hospital mortality (OR 0.54, 95% CI 0.38-0.75) and 30-day readmission (OR 0.79, 95%CI 0.64-0.98). Hospital volume remained an independent predictor of 30-day readmission for emergent admissions (OR 0.72, 95% CI 0.61-0.85) and in-hospital mortality for nonemergent admissions (OR 0.39, 95% CI 0.19-0.82). CONCLUSION: Patients undergoing abdominal surgery for CD have lower odds of postoperative mortality and 30-day readmission when the operation occurs at a high-volume hospital. These findings suggest that surgical patients with CD may benefit from care at specialized centres.

Discounting Health Grades for Disparity: The 2021 Wisconsin Population Health and Equity Report Card.

We describe updates to the University of Wisconsin Population Health Institute's methodology for a state health report card, first described in Preventing Chronic Disease in 2010, and the considerations that were weighed in making those updates. These methods have been used since 2006 to issue a periodic report entitled Health of Wisconsin Report Card. The report highlights Wisconsin's standing among other states and serves as an example for others seeking to measure and improve their population's health. For 2021, we revisited our approach with an increased emphasis on disparities and health equity, which required many choices about data, analysis, and reporting methods. In this article, we outline the decisions, rationale, and implications of several choices we made in assessing Wisconsin's health by answering several questions, among them: Who is the intended audience and which measures of length (eg, mortality rate, years of potential life lost) and quality of life (eg, self-reported health, quality-adjusted life years) are most relevant to them? Which subgroups should we report disparities about, and which metric is most easily understood? Should disparities be summarized with overall health or reported separately? Although these decisions are applicable to 1 state, the rationale for our choices could be applied to other states, communities, and nations. Consideration of the purpose, audience, and context for health and equity policy making is important in developing report cards and other tools that can improve the health of all people and places.

Ecological Study of Urbanicity and Self-reported Poor Mental Health Days Across US Counties.

Geography may influence mental health by inducing changes to social and physical environmental and health-related factors. This understanding is largely based on older studies from Western Europe. We sought to quantify contemporary relationships between urbanicity and self-reported poor mental health days in US counties. We performed regression on US counties (n = 3142) using data from the County Health Rankings and Roadmaps. Controlling for state, age, income, education, and race/ethnicity, large central metro counties reported 0.24 fewer average poor mental health days than small metro counties (t = - 5.78, df = 423, p < .001). Noncore counties had 0.07 more average poor mental health days than small metro counties (t = 3.06, df = 1690, p = 0.002). Better mental health in large central metro counties was partly mediated by differences in the built environment, such as better food environments. Poorer mental health in noncore counties was not mediated by considered mediators.

COVID-19 deaths in children and young people in England, March 2020 to December 2021: An active prospective national surveillance study.

BACKGROUND: Coronavirus Disease 2019 (COVID-19) deaths are rare in children and young people (CYP). The high rates of asymptomatic and mild infections complicate assessment of cause of death in CYP. We assessed the cause of death in all CYP with a positive Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) test since the start of the pandemic in England. METHODS AND FINDINGS: CYP aged <20 years who died within 100 days of laboratory-confirmed SARS-CoV-2 infection between 01 March 2020 and 31 December 2021 in England were followed up in detail, using national databases, surveillance questionnaires, post-mortem reports, and clinician interviews. There were 185 deaths during the 22-month follow-up and 81 (43.8%) were due to COVID-19. Compared to non-COVID-19 deaths in CYP with a positive SARS-CoV-2 test, death due to COVID-19 was independently associated with older age (aOR 1.06 95% confidence interval (CI) 1.01 to 1.11, p = 0.02) and underlying comorbidities (aOR 2.52 95% CI 1.27 to 5.01, p = 0.008), after adjusting for age, sex, ethnicity group, and underlying conditions, with a shorter interval between SARS-CoV-2 testing and death. Half the COVID-19 deaths (41/81, 50.6%) occurred within 7 days of confirmation of SARS-CoV-2 infection and 91% (74/81) within 30 days. Of the COVID-19 deaths, 61 (75.3%) had an underlying condition, especially severe neurodisability (n = 27) and immunocompromising conditions (n = 12). Over the 22-month surveillance period, SARS-CoV-2 was responsible for 1.2% (81/6,790) of all deaths in CYP aged <20 years, with an infection fatality rate of 0.70/100,000 SARS-CoV-2 infections in this age group estimated through real-time, nowcasting modelling, and a mortality rate of 0.61/100,000. Limitations include possible under-ascertainment of deaths in CYP who were not tested for SARS-CoV-2 and lack of direct access to clinical data for hospitalised CYP. CONCLUSIONS: COVID-19 deaths remain extremely rare in CYP, with most fatalities occurring within 30 days of infection and in children with specific underlying conditions.

Autoregulation of H+/lactate efflux prevents monocarboxylate transport (MCT) inhibitors from reducing glycolytic lactic acid production.

BACKGROUND: Pharmacological inhibition of membrane transporters is expected to reduce the flow of solutes, unless flux is restored (i.e., autoregulated) through a compensatory increase in the transmembrane driving force. Drugs acting on monocarboxylate transporters (MCTs) have been developed to disrupt glycolytic metabolism, but autoregulation would render such interventions ineffective. We evaluated whether small-molecule MCT inhibitors reduce cellular H+/lactate production. METHODS: Cellular assays measured the relationship between MCT activity (expressed as membrane H+/lactate permeability; PHLac) and lactic acid production (inferred from H+ and lactate excretion; JHLac) in a panel of pancreatic ductal adenocarcinoma (PDAC) cells spanning a range of glycolytic phenotype. RESULTS: MCT activity did not correlate with lactic acid production, indicating that it is not set by membrane permeability properties. MCT inhibitors did not proportionately reduce JHLac because of a compensatory increase in the transmembrane [lactate] driving force. JHLac was largely insensitive to [lactate], therefore its cytoplasmic build-up upon MCT inhibition does not hinder glycolytic production. Extracellular acidity, an MCT inhibitor, reduced JHLac but this was via cytoplasmic acidification blocking glycolytic enzymes. CONCLUSIONS: We provide mathematically verified evidence that pharmacological and physiological modulators of MCTs cannot proportionately reduce lactic acid production because of the stabilising effect of autoregulation on overall flux.

Death by Choking or Dysphagia: A Review of Coronial Findings (Australia and Canada): A Picture of Preventable Death, Non-adherence to Written Recommendations, and Lack of Appropriate Supervision.

Choking and aspiration pneumonia are a leading cause of preventable death for people in residential care in Australia. In Victoria, in 2018-2019, 59% of deaths of persons in residential care that were referred to the coroner were from aspiration pneumonia. In 2016-2017, in New South Wales, the leading cause of death in people with disability living in residential care was pneumonitis caused by solids and fluids in the lungs. Such deaths are closely linked with swallowing problems (dysphagia) and people with cognitive impairments and multiple health issues, including mental health issues, are most at risk. This commentary focuses on coronial inquests where coroners' findings have identified dysphagia or aspiration pneumonia as a cause of death or a contributor to a person's death. It also includes a summary of the recommendations by coroners which highlight processes that should be implemented to improve the safety of people with dysphagia.